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Mast Cell Tissue Inhibitor of Metalloproteinase-1 Is Cleaved and Inactivated Extracellularly by -Chymase¹

Brendon T. Frank^*, J. Caleb Rossall^*, George H. Caughey^*, and Kenneth C. Fang^2,*,

^* Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, CA 94143

We previously reported that mast cell -chymase cleaves and activates progelatinase B (progel B). Outside of cells, progel B is complexed with tissue inhibitor of metalloproteinase (TIMP)-1, which hinders zymogen activation and inhibits activity of mature forms. The current work demonstrates that dog BR mastocytoma cells, HMC-1 cells, and murine bone marrow-derived mast cells secrete TIMP-1 whose electrophoretic profile in supernatants suggests degranulation-dependent proteolysis. -Chymase cleaves uncomplexed TIMP-1, reducing its ability to inhibit gel B, whereas tryptase has no effect. Sequencing of TIMP-1’s -chymase-mediated cleavage products reveals hydrolysis at Phe¹²-Cys¹³ and Phe²³-Val²⁴ in loop 1 and Phe¹⁰¹-Val¹⁰² and Trp¹⁰⁵-Asn¹⁰⁶ in loop 3 of the NH₂-terminal domain. TIMP-1 in a ternary complex with progel B and neutrophil gelatinase-associated lipocalin is also susceptible to -chymase cleavage, yielding products like those resulting from processing of free TIMP-1. Thus, -chymase cleaves free and gel B-bound TIMP-1. Incubation of the progel B-TIMP-1-neutrophil gelatinase-associated lipocalin complex with -chymase increases gel B activity 2- to 5-fold, suggesting that -chymase activates progel B whether it exists as free monomer or as a complex with TIMP-1. Furthermore, inhibition of -chymase blocks degranulation-induced TIMP-1 processing (absent in -chymase-deficient HMC-1 cells). Purified -chymase processes TIMP-1 in BR supernatants, generating products like those induced by degranulation. In summary, these results suggest that controlled exocytosis of mast cell -chymase activates progel B even in the presence of TIMP-1. This is the first identification of a protease that overcomes inhibition by bound TIMP-1 to activate progel B without involvement of other proteases.

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